Method of producing a concentrate comprising a sulfonamide in solution, a 2,4-diaminopyrimidine in stable suspension within said solution

ABSTRACT

A palatable antimicrobial drug concentrate comprising: (a) a sulfonamide and/or sulfonamide salt in aqueous solution; (b) a 2,4-diaminopyrimidine in stable suspension within said solution; and (c) a suspending agent. The invention has a long room temperature shelf life and is sufficiently stable to be administered via the drinking water of animals.

This application is a continuation of application Ser. No. 09/780,371,filed on Feb. 12, 2001 now U.S. Pat. No. 6,410,543, which is acontinuation of application Ser. No. 09/304,954 filed on May 5, 1999,now U.S. Pat. No. 6,211,185, which is assigned to the assignee of thepresent invention, and which is incorporated herein.

FIELD OF THE INVENTION

The instant invention relates to an antimicrobial concentrate thatcomprises a sulfonamide and/or sulfonamide salt in combination with adiaminopyrimidine. More specifically, the instant invention relates to apalatable antimicrobial concentrate, that may be orally administered toanimals via their drinking water, that comprises the followingcomponents: (a) a sulfonamide and/or salt thereof in solution; (b) adiaminopyrimidine in stable suspension within said solution; and (c) asuspending agent.

BACKGROUND ART

The use of sulfonamides (sulfa drugs) for treating bacterial infectionsis known. The Merk Veterinary Manual, sixth edition, 1986, pages 1540through 1544, provides general background on these drugs. It is believedthat sulfonamides are effective antibacterial agents because theycompetitively inhibit an enzymatic step (dihydropterate synthetase)wherein para-aminobenzoic acid is incorporated into the synthesis ofdihydrofolic acid (folic acid). Because folic acid synthesis is reduced,the level of tetrahydrofolic acid (folinic acid) formed from folic acidis also reduced. Folinic acid is an essential component of variouscoenzymes responsible for single carbon metabolism in cells. Thus,sulfonamides create a domino effect in the body that ultimately resultsin the suppression of protein synthesis, the impairment of metabolicprocesses, and an inhibition in the growth and multiplication oforganisms that cannot utilize preformed folic acid. The effect isbacteriostatic and, in high concentrations, bactericidal.

2,4-Diaminopyrimidines, such as trimethoprim, are also knownantimicrobial agents that have found utility in the treatment of variousbacterial and protozoal infections. U.S. Pat. Nos. 2,909,522 and3,021,332 are two references directed to the formation and use of2,4-diaminopyrimidines. It is believed that these compounds act byinhibiting an enzyme that facilitates the conversion of folic acid tofolinic acid and, thereby, interfering with the biosynthesis of nucleicacids and proteins in bacteria. Typically, 2,4-diaminopyrimidines have ahigh selectivity for inhibiting the folate synthesis in protozoalenzymes as opposed to folate coenzyme synthesis in host cells. Thus,2,4-diaminopyrimidines are widely used in veterinary antimicrobialcompositions.

When sulfonamides are combined with 2,4-diaminopyrimidines, asynergistic antimicrobial effect is often obtained. Although theenhancement in antimicrobial activity is mutual, the2,4-diaminopyrimidines are often referred to as sulphonamidepotentiators. This synergistic antimicrobial activity is very effectiveagainst gram-positive and gram-negative bacterial pathogens. The MerkVeterinary Manual, sixth edition, 1986, pages 1544 through 1546,provides general background information on this drug combination.

It would be desirable to combine sulfonamides with2,4-diaminopyrimidines in a stable palatable concentrate that could beeffectively administered to animals via their drinking water, e.g.,through the automatic water and Tank water systems utilized in livestockfacilities. This type of administration is the most cost effective meansof treating large animal populations. Other techniques, such asinjection, directly administering tablets or fluids, and powder/foodmixtures, have numerous drawbacks. Injection is time consuming, costly,and potentially hazardous because the needle can break off in the animaland/or create an infective injection site. Force feeding tablets andfluids directly to an animal is, minimally, a taxing chore. Mixingsulfonamide and 2,4-diaminopyrimidine powders into an animal's foodcreates a bad tasting mixture that the animal is less likely to ingest,making it difficult to insure that even dosages are administered.

Unfortunately, 2,4-diaminopyrimidines and many sulfonamides exhibit poorsolubility in water. Although techniques exist to increase thesolubility of each compound individually, these techniques areincompatible. Sulfonamides are solubilized in water by the addition of apharmaceutically acceptable inorganic base whereas2,4-diaminopyrimidines are solubilized in water by the addition of apharmaceutically acceptable acid. If the acidic and basic solutions aremixed, the sulfonamide and 2,4-diaminopyrimidine components precipitateout of solution.

Furthermore, in aqueous compositions where the pH approaches 7.0,sulfonamides and 2,4-diaminopyrimidines combine, in a 1 to 1 molarratio, to form an insoluble and undesirable complex. Given that citywater generally has a pH between 7.0 and 7.5, the formation of thiscomplex is hard to avoid when the two compounds are placed intoautomatic or Tank water systems.

Attempts have been made to generate aqueous solutions containing bothsulfonamides and 2,4-diaminopyrimidines by adding various types ofwater-miscible organic solvents, such as dimethylacetamide and lowmolecular weight polyalkylene glycols. U.S. Pat. Nos. 3,985,876,4,031,214, and 4,089,949 are representative of this art. Thesesolutions, which are primarily utilized in injection procedures, are notsuitable for use in automatic water and Tank water facilities. Theorganic solvent's ability to promote solubility is quickly diminished bylarge scale dilution in water. Furthermore, large scale dilution inwater typically brings the pH near 7.0, which is often outside the pHparameters necessary to maintain the solutions.

Compositions containing sulfonamides in solution and2,4-diaminopyrimidine potentiators in suspension have also been made.U.S. Pat. Nos. 4,031,214 and 4,332,796 are representative of this art.

U.S. Pat. No. 4,031,214 describes an injectable preparation thatcomprises a suspension of finely divided potentiator within an aqueoussolution containing a pharmaceutically acceptable water soluble salt ofa sulphonamide and a strong base. The term potentiator is defined in thepatent to include many types of 2,4-diaminopyrimidines. The pH of thepreparation is stated to be at least 10 to avoid the growth ofcrystalline complexes. U.S. Pat. No. 4,031,214 does not disclose thatthe composition can be orally administered either directly or throughdrinking water. Furthermore, the patent does not disclose a suspendingagent. Finally, it is clear from the pH parameters required in thepatent that the composition described therein would not be useful inlivestock drinking water where the pH typically approaches 7.0.

U.S. Pat. No. 4,332,796 describes potentiated sulfonamide compositionsuseful for intramuscular injection. The compositions comprise mixturesof alkali metal sulfonamides with microcrystalline potentiators whereinthe microcrystals have been coated with mixtures of phospholipids andnon-ionic surfactants. The compositions are alleged to be advantageousbecause they can be used for injection with the addition of sterilewater. Furthermore, it is alleged that the resulting aqueouspreparations are stable for long periods of time. The potentiatorcomponent preferably belongs to the 2,4-diaminopyrimidine class ofcompounds. The injectable mixture, with sterile water, has a pH in theadvantageous range of 8.5-9.5. U.S. Pat. No. 4,332,796 does not disclosethat the composition can be orally administered either directly orthrough drinking water. Furthermore, the patent does not disclose theuse of a suspending agent. In fact, the reference teaches thatsuspending agents are undesirable because they provoke irritation at theinjection site, lower chemotherapeutic diffusion in tissues and adecrease in injectability. Finally, it is clear from the high pHparameters required by the patent that the composition described thereinwould not be useful in livestock drinking water where the pH typicallyapproaches 7.0.

Thus, there remains a need in the art for an antimicrobial concentratethat comprises a sulfonamide and/or salt thereof in combination with adiaminopyrimidine that may be orally administered to animals via theirdrinking water. To be economically feasible, the concentrate would havea room temperature shelf life of at least several days. In addition,when the concentrate is diluted in sufficient water to bring the pH near7.0, the components in the concentrate would have to remain dissolvedand/or suspended for at least a day.

SUMMARY OF THE INVENTION

The invention is a palatable antimicrobial drug concentrate that can beorally administered to an animal in combination with its drinking water,comprising: (a) a sulfonamide and/or sulfonamide salt in aqueoussolution; (b) a 2,4-diaminopyrimidine in stable suspension within saidsolution; and (c) a suspending agent. The aqueous solution is preferablyorganic solvent free. Component (a) is most preferably sodiumsulfadiazine. Component (b) is most preferably micronized orultramicronized trimethoprim. Component (c) is most preferably xanthangum. The palatibility of the 2,4-diaminopyrimidine in the concentrationis improved by coating, sweetening and flavoring the suspended2,4-diaminopyrimidine to reduce its adverse taste. The concentrateexhibits a long term room temperature shelf life which exceeds 10 daysand often is best measured in years. In addition, the components of theconcentrate, when diluted by water to a pH within the range of 7.0 to7.5, remain stable for at least 24 hours.

DISCLOSURE OF THE INVENTION

The instant invention relates to a antimicrobial concentrate comprisinga suspension of a 2,4-diaminopyrimidine in an aqueous solutioncontaining a sulfonamide and/or sulfonamide salt. From the perspectiveof taste, it is preferred that the 2,4-diaminopyrimidine be in the formof a suspension since this better masks the bitter taste of the drug.

The concentrate contains three critical components in addition to thewater carrier. The first component is a sulfonamide and/or sulfonamidesalt in aqueous solution. The second component is a2,4-diaminopyrimidine suspended within said aqueous solution. The thirdcomponent is a suspending agent which coats the 2,4-diaminopyrimidinecompound and enhances the stability of the suspension. In addition, anumber of other optional components are preferably added. These optionalcomponents include antioxidants, preservatives, surfactants, sweeteners,and flavoring agents.

The sulfonamide is added as an antimicrobial agent and any sulfonamideknown in the art for this purpose may be utilized in the instantinvention. Sulfonamides, also known as sulfa drugs, are generallyderived from sulfanilic acid and are represented by the followingformulae (i) through (iv):

wherein n equals zero or one and X, if present, is a phenyl moiety, andwherein R₁ through R₈ are, independently, selected from hydrogen and anyorganic moiety containing up to 20 atoms.

Sulfonamides corresponding to formulae (i) through (iv) includedisulfamethoxypyridazine, sulfacetamide, sulfamidochyrsoidine,sulfanilamide, 4-sulfanilamidosalicylic acid,N⁴-sulfanilylsulfanilamide, sufanilylurea, N-sulfanilyl-3,4-xylamide,2-p-sulfanilylanilinoethanol, sulfabenz, sulfabenzamide, sulfacytine,sulfachrysoidine, sulfadiazine, sulfadicramide, sulfadimethoxine,sulfadoxine, sulfaethidole, sulfaethoxypyridazine, sulfafurazole,sulfaguanole, sulfisomidine, sulfisoxazole, sulfalene, sulfaloxic acid,sulfamerazine, sulfameter, sulfamethazine, sulfamethoxypyridazine,sulfanitran, sulfapyridazine, sulfamethoxazole, sulfamethylthiazole,sulfametrole, sulfamoxole, sulfamethizole, sulfamethomidine,sulfaoxazole, sulfaperine, sulfaphenazole, sulfaproxyline,sulfapyrazine, sulfapyridine, sulfaquanidine, sulfaquinoxaline,sulfasomizole, sulfasymazine, sulfasalizine, sulfatolamide,sulfathiazole, sulfathiourea, sulfatolamide, sulfazamet, halogen and/orC₁₋₄ alkyl substituted variations thereof, and the like.

Preferably, either all of the R₁₋₈ groups present on the sulfonamidesare hydrogen or all but one of the R₁₋₈ are hydrogen. More preferably,the sulfonamides are represented by the following formula (v):

wherein n is one or zero, X is a phenyl moiety, and R is hydrogen or anorganic moiety containing up to 20 atoms. These more preferred sulfadrugs exhibit the best balance between effectiveness and cost. The mostpreferred sulfonamides are sulfadiazine, sulfanilamide, sulfisoxazole,sulfaoxazole, and sulfapyridine, with sulfadiazine being the sulfa drugof choice.

The sulfonamides may be salified to increase their water solubility. Infact, this is a necessary step if water insoluble, or only slightlysoluble, sulfonamides are employed. The salts may be prepared by avariety of known techniques. For example, the sulfonamide may bedissolved in an alcoholic medium followed by the addition of an alkalihydroxide alcoholic solution causing the desired salt to precipitate outof solution. Alternatively, it is also possible to combine the processfor making the sulfonamide salt with the process for making theinventive concentration by reaction of the sulfonamide with bases inaqueous solution. Substances that can be used to form such salts are,for example, all alkalies (preferably sodium hydroxide), and organicamines (preferably alkanolamines such as ethanolamine,tri(hydroxymethyl)aminomethane and diethanolamine).

For example, the most preferred sulfonamide for use in this invention issulfadiazine. Sulfadiazine is only slightly soluble in water. Therefore,sulfadiazine is generally added in the form of an alkali metal salt suchas sodium sulfadiazine and optionally in combination with a base such asdiethanolamine.

The sulfonamide in this invention is present in an amount of at least 2%and no more than 55%, based on the entire weight of the composition.Preferably, the sulfonamide represents 25% to 50% of the composition.Most preferably, the sulfonamide is 45% to 50%_of the composition.

The 2,4-diaminopyrimidine is also added as an antimicrobial agent and,preferably, serves as potentiator for the sulfonamide. Any known2,4-diaminopyrimidine may be utilized in the invention. Preferred 2,4diaminopyrimidines include 2,4-diamino-5-benzylpyrimidines having thefollowing formula (vi):

wherein Y₁ is hydrogen or an alkyl having four or less carbon atoms, andwherein Z₁-5 are, independently, selected from hydrogen, an alkoxy grouphaving four or less carbon atoms such as methoxy and isobutoxy, an aminogroup, a nitro group, halogens such as chlorine and bromine, an alkyl orsubstituted alkyl group having four or less carbon atoms such as methyland trifluoromethyl, and a hydroxyl group. Suitable preferredpotentiators corresponding to the preceding formula include2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine (a.k.a. trimethoprim),2,4-diamino-5-(3,4-dimethoxybenzyl) pyrimidine (a.k.a. diaveridine), 2,4diamino-5-(3,4,6-trimethoxybenzyl) pyrimidine,2,4-diamino-5-(2-methyl-4,5-dimethoxybenzyl) pyrimidine (a.k.a.ormetoprim), 2,4-diamino-5-(3,4-dimethoxy-5-bromobenzyl) pyrimidine, and2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidine (a.k.a. pyrimethamine).The most preferred 2,4-diaminopyrimidine it trimethoprim.

The 2,4-diaminopyrimidine is preferably added in particulate micronizedor ultramicronized form. By micronized, it is meant that the2,4-diaminopyrimidine has a particle size (average diameter) within therange of 1μ to 100μ. Ultramicronized particles are a subgroup ofmicronized particles and have a particle size of 0.25μ to 10μ. As thetrimethoprim particle size gets smaller, it becomes easier to maintainthe suspension.

The 2,4-diaminopyrimidine in this invention is present in an amount ofat least 0.4%_and no more than 18.5%, based on the entire weight of theconcentrate. Preferably, the 2,4-diaminopyrimidine represents 5% to16.5% of the concentrate. Most preferably, the 2,4-diaminopyrimidine is9.0% to 10% of the concentrate.

The ratio of sulfonamide and/or sulfonamide salt to2,4-diaminopyrimidine in the concentrate can range from 10:1 to 0.1:1(w/w). Preferably, however, the ratio of sulfonamide and/or salt thereofto 2,4-diaminopyrimidine is approximately 3:1 to 5:1. The most preferredratio of sulfonamide and/or salt thereof to 2,4-diaminopyrimidine isapproximately 4:1.

The suspending agent is added to coat the suspended particles and,thereby, prevent them from sticking together. When particles sticktogether they become heavier and more easiliy fall out of suspension.The suspending agent not only stabilizes the suspension but also permitsa higher percentage of suspended particles to be incorporated into thesuspension.

Any pharmaceutically acceptable suspending agent may be employed in theinvention including water soluble polysaccharide gums and cellulosederivatives such as methyl cellulose, carboxymethylcellulose andhydroxypropylmethylcellulose. However, the water soluble polysaccharidegums have proven to give superior results. Suitable water solublepolysaccharide gums include xanthan gum, guar gum, and gum arabic.

In particular, it has been discovered that xanthan gum generates thehighest suspension stability and, thereby, enables higher concentrationsof 2,4-diaminopyrimidine to be maintained in suspension. Xanthan gum isa high molecular weight heteropolysaccharide composed of D-glucose,D-mannose, and D-glucuronic acid. Numerous studies indicate that xanthangum has a molecular weight of approximately 2 million. Xanthan gumdissolves in acidic solutions, is compatible with most basic compounds,and exhibits unusual stability in the presence of most salts.

The suspending agent in this invention is present in an amount of atleast 0% and no more than 5%, based on the entire weight of theconcentrate. Preferably, the suspending agent represents 0% to 2% of theconcentrate. Most preferably, the suspending agent is 0% to_(—)0.35% ofthe concentrate.

Preferably, surfactants (surface active agents) are also added in orderto increase the spreading and wetting properties. In general, surfactantmolecules have two dissimilar ends. One end is water soluble (highlypolar or hydrophillic) and the other end is water insoluble (non-polaror hydrophobic). At the particle-water interface, the hydrophillic groupwill associate with the water and the hydrophobic end with the particle.This action reduces surface tension and aids suspension of the particlesin the water. Surfactants are classified as anionic, cationic andnon-ionic depending on the electric charge of their active groups.

Any pharmaceutically acceptable surfactant known in the prior art may beused in the invention. Preferably the surfactants are nonionicsurfactants. Particularly preferred nonionic surfactants arepolysorbates. Polysorbates are polyoxethylene fatty acid esters.Polysorbates are obtained by the esterification of sorbitol with a fattyacid such as stearic acid, lauric acid and palmitic acid underconditions that cause splitting out of water from the sorbitol, leavingsorbitan. About 20 moles of ethylene oxide per mole of sorbitol are usedin the condensation to effect water solution. Suitable polysorbatesinclude polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate),polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate65 (polyoxyethylene (20) sorbitan tristearate), and polysorbate 80(polyoxyethylene (20) sorbitan monooleate). A preferred surfactant ispolysorbate 80.

When surfactants are employed, they are generally present in an amountof at least 0% and no more than 3%, based on the entire weight of theconcentrate. Preferably, the surfactants represent 0% to 2% of theconcentrate. Most preferably, the surfactants are 0% to_(—)1.697% of theconcentrate.

Preferably, sweeteners are also added to counter the bitter taste of the2,4-diaminopyrimidine. The sweeteners are selected from any naturaland/or synthetic compounds capable of overcoming the bitterness of thedrug. Natural sweeteners include carbohydrates such as sucrose,dextrose, fructose, invert sugar, mannitol, sorbitol, and the like.Synthetic sweeteners include saccharin, aspartame, cyclamates, and otherso-called artificial sweeteners that are familiar to those of skill inthe art.

When a sweeteners are employed, they are generally present in an amountof at least 0% and no more than 65%, based on the entire weight of theconcentrate. Preferably, the sweeteners represent 0% to 5% of theconcentrate. Most preferably, the sweeteners are 0% to_(—)2% of theconcentrate.

Preferably, flavoring agents are also added to give the2,4-diaminopyrimidine a recognizable and pleasing taste. The flavoringagents may be any natural or synthetic compounds that provide anacceptable taste to the composition. Such flavoring agents includebubble gum, fruit flavorings (such as grape, cherry, berry, and citrus),mint flavorings (such as peppermint and spearmint), vanilla, chocolate,and the like.

When flavoring agents are employed, they are generally present in anamount of at least 0% and no more than 10%, based on the entire weightof the concentrate. Preferably, the flavoring agents represent 0.1% to5% of the concentrate. Most preferably, the flavoring agents are 0.25%to 0.44% of the concentrate.

Preferably, antioxidants are employed in the invention to preventoxidation of the antimicrobial agent(s) in the presence of oxygen. Anypharmaceutical grade antioxidants that dissolve into the solution of theinvention cant be used. Examples of antioxidants useful in the inventioninclude sodium metabisulfate, ascorbic acid, sodium formaldehyde,sulfoxylate, or mixtures thereof. A preferred antioxidant is sodiummetabisulfate.

When antioxidants are employed, they are generally present in an amountof at least 0% and no more than 5%, based on the entire weight of theconcentrate. Preferably, the antioxidants represent 0.1% to 0.2% of theconcentrate. Most preferably, the antioxidants are 0.12% to 0.1334% ofthe concentrate.

Preferably, preservatives are used in order to extend the shelf life ofthe liquid pharmaceutical solutions of the invention by limiting theamount of microorganisms in the solution. Any type of pharmaceuticalgrade preservatives that are completely soluble in the solution of theinvention are useful. Examples of suitable preservatives include butylparaben, methylparaben, polyparaben, and mixtures thereof.

When preservatives are employed, they are generally present in an amountof at least 0% and no more than 1.0%, based on the entire weight of theconcentrate. Preferably, the preservatives represent 0% to 0.01% of theconcentrate. Most preferably, the preservatives are 0% to 0.008% of theconcentrate.

The principal carrier for the concentrate is water. Preferably, thewater is substantially organic solvent free and, more preferably,completely organic solvent free. By “substantially organic solvent free”it is meant that organic solvents make up no more than 5% of theconcentrate. Organic solvents are undesirable because they effect thetaste of the concentrate and, when mixed, they are not stable in thetime range of 8-12 hours.

There is no real limit to the amount of water that can be employed inthe concentrate as long as sufficient water is employed to maintain thesulfonamide and/or sulfonamide salt in solution and the2,4-diaminopyrimidine in suspension. However, since the composition is aconcentrate, it is preferred to limit the water as much as possible toreduce the size of the product to aid handling and storage.

Generally, the water carrier is present in an amount of at least 40% andno more than 90%, based on the entire weight of the concentrate.Preferably, the water represents 50% to 80% of the concentrate. Mostpreferably, the water is 65% to 70% of the concentrate.

The pH of the concentrate will obviously depend on a number of factors,including the water concentration. However, generally, the concentratehas a pH at or above 10.

One of the benefits of the concentrate is that it exhibits a long shelflife at room temperature. By “shelf life” it is meant that thesulfonamide or sulfonamide salt stays in solution, that the2,4-diaminopyrimidine stays in suspension, and that both of thesecomponents maintain their antimicrobial properties. Depending on thecomponents and concentrations, the shelf life of the concentrates madein accordance with the invention ranges from at least 10 days to threeyears or more at room temperature.

Any animal may be treated with the composition. Suitable animals includehumans, domestic animals (such as livestock, e.g., pigs, beef and dairycattle, horses, poultry, and sheep), pets (such as dogs, cats, and thelike), and non-domestic animals such as deer, buffalo, elk, and thelike, that are kept in herds and fed from a controlled water supply.

A major benefit of the concentrate is that it can be effectivelyadministered by dilution into the drinking water of large animalpopulations, e.g. addition into the automatic water and Tank systems inlivestock facilities. City water generally has a pH between 6.0 and 8.0.Therefore, it is necessary in such applications that the components inthe diluted concentrate remain stable over the entire pH range of 7.0 to7.5. By “stable”, it is meant that for at least 24 hours after theconcentrate has been diluted with water, the sulfonamide or sulfonamidesalt remains in solution, the 2,4-diaminopyrimidine remains insuspension, and there is no appreciable complex formation. It has beendiscovered that the compositions of the instant invention remain stablefor at least 12, and often 96 hours or more, when diluted withsufficient water to bring the pH within the range of 7.0 to 7.5.

The dosage of concentrate that is administered is guided by the judgmentof the health care provider after taking into consideration a number offactors including the type of animal, the size of the animal, the typeof infection being treated, and whether the treatment is preemptive orresponsive to an existing condition. However, the dosage should alwaysbe such that the targeted gram positive or gram negative bacterialinfection or infections can be treated. These types of bacteria include:Steptococci; Staphylococci; actinobacillie; actinomyceae; Salmonella;Pasteurella; Pneumococci; Proteus; E. Coli; Coynebacteria; Vibrio;Bordetelle; Brucella; Klebsiellae; Haemophilae; and Enterobacter speciessuch as Morganella, Shigella and Pneumocystis Carinii.

Preferably, however, the dosage of concentrate to final drinking wateris 1 ounce of concentrate per gallon of drinking water. More preferably,the dosage is 300 ml of concentrate per gallon of stock solution thefirst day of treatment and 150 ml of concentrate per gallon of stocksolution on each day thereafter.

The following examples are intended to illustrate, but not limit, theinvention:

EXAMPLE 1 Formation of First Inventive Concentration

80 gm sodium metabisulfate, 760 ml diethanolamine, 76 ml polysorbate 80,3600 ml concentrated sodium saccharin, and 250 ml cherry concentratewere added to 45,000 ml of deionized water. The solution was stirreduntil all of the components were dissolved. 25 Kg of sodium sulfadiazinewas then slowly added, followed by approximately 30 minutes of stirringto insure that the sodium sulfadiazine dissolved into the solution. Thesolution was then diluted to 60,000 ml with deionized water and filteredtwice through a coarse filter. 6800 gm of trimethoprim having a particlesize of 14μ was added followed by thorough stirring to suspend thetrimethoprim in the solution. 200 gm of xanthan gum was then added andthe composition was vigorously stirred until the xanthan gum becamefully hydrated and all of the trimethoprim particles were coated. Thecomposition was then diluted to 68200 ml with deionized water anddispensed into containers The final mixture has 400 mg/ml sulfadiazineand 100 mg/ml trimethoprim.

EXAMPLE 2 Formation of Second Inventive Concentration

A composition was formulated in the same manner set forth in Example 1with the exception that the particle size of the trimethoprim is lessthan 4 microns. Note that although 200 gm xanthan gum was once againutilized, the lower particle size of the trimethoprim would havepermitted a substantial lowering in the amount of xanthan gum employed.This formulation enabled a longer duration suspension—up to 96 hours instock solution and several weeks in the concentrate.

EXAMPLE 3 Formation of Comparative Concentration

A composition was made in accordance with Example 1 with the exceptionthat no xanthan gum was employed.

EXAMPLE 4

The inventive and comparative concentrations created in Examples 1, 2and 3 were added to six 128 gallon samples of drinking water. The sixsamples included 150 ml per gallon and 300 ml per gallon samples of theinventive concentration from Example 1, 150 ml per gallon and 300 ml pergallon samples of the inventive concentration from Example 2, and 150 mland 300 ml per gallon samples of the comparative concentration inExample 3. The 150 ml gallon samples are 12.89 mg/kg dosages of the drugand the 300 ml per gallon samples are 25.78 mg/kg dosages of the drug.

A field trial using pigs was then conducted to compare the effectivenessof the concentrations. In the trial, the 12.89 mg/kg dosages were usedin the first day and the 25.78 mg/kg dosages were used in days 2 to 7.The results are summarized in the following Table 1:

TABLE 1 Water Dose as Dose as consumed per delivered per pig deliveredper pig day by 1000 (150 cc per gallon (300 cc per gallon Treatment 30lb. pigs of stock water) of stock water) Example 1 395 gallons 231.44 mg462.88 mg Example 2 398 gallons 233.20 mg 466.40 mg Control (no 402gallons N/A N/A treatment) Example 3 (no 301 gallons 176.37 mg 352.74 mgxanthan coating)

The trimethoprim in the comparative Example 3 formulation dropped out ofsuspension within 20 minutes to one hour. In contrast, the formulationsof Examples 1 and 2 remained in suspension for the full day of eachadministration. As evidenced by Table 1, the net result was the abilityto maintain the suspension for a longer duration allowed the pigs toinjest more of the antimicrobial formulation in Examples 1 and 2.

EXAMPLE 5

A field trial was conducted comparing the effectiveness of 50 cc of theconcentration in Example 1 versus 454 cc of a commercially availablesulfamethoxizole/trimethoprim suspension that is utilized in humanpediatric medicine (herein referenced as “Smz/Tmp Human”). Thecomparison related to the treatment of a bacterial respiratory diseasein pigs caused by Haemophilis Parasuis and Pasturella Multocida.Sensitivity was confirmed to both preparations by bacteriology. Theresults are outlined in the following Table 2:

TABLE 2 Number of Number Mortalities Animals of Sick after 14 DaysNumber of in the Animals in of Treatment Culls at Treatment Group theGroup due to Sickness Slaughter Example 1 508 263  3  6 Smz/Tmp 502 27535 28 Human Control (no 506 269 52 32 treatment)

Note that it is impossible to dose more than 3 pints of Smz/Tmp Humansuspension per gallon of stock solution and that the trimethoprim in theSmz/Tmp Human suspension falls out of suspension within 5 minutesresulting in severe under dosing of the product as compared to theinventive concentration from Example 1. Thus the Smz/Tmp Human treatmentis 11 to 12 time more ineffective in preventing mortality. This was oneof the principle motivators behind the development of the invention.

EXAMPLE 6

The efficacy of the inventive embodiment described in Example 2 andSmz/Tmp Human against E. Coli K-88 serotype in 25 pound nursery pigswith diarrhea. The process was substantially identical to the processdescribed in the preceding Example 5. Note that Smz/Tmp Human is theproduct currently being used commercially. The results are set forth inthe following Table 3:

TABLE 3 Mortality Number of in pigs after Mortality in pigs Treatmentpigs in group treatment started prior to treatment Example 2 325  2 185Smz/Tmp Human 325 24 182 Control (no 50  5  25 treatment)

This demonstration demonstrates the superior dosing and consequently thesuperior efficacy of the inventive formulations compared to traditionsulfonamide/trimethoprim suspension treatments.

While the invention has been described in conjunction with the specificembodiments outlined above, it is evident that many alternatives,modifications, and variations will be apparent to those skilled in theart. In example, some steps may be eliminated or performed out ofsequence. Accordingly, the preferred embodiments of the invention areintended to be illustrative and not limiting. Various changes may bemade without departing from the spirit and scope of the invention asdefined in the claims.

What is claimed is:
 1. A palatable antimicrobial drug concentrate, thatmay be orally administered to an animal in combination with its drinkingwater, comprising a 2,4-diaminopyrimidine in stable suspension, asuspending agent, and a sulfonamide, wherein the sulfonamide is selectedfrom the compounds corresponding to the following formula:

wherein n equals zero or one and X, if present, is a phenyl moiety, andwherein R₂ through R₆ are, independently, selected from hydrogen and anyorganic moiety containing up to 20 atoms.
 2. A palatable antimicrobialdrug concentrate, that may be orally administered to an animal incombination with its drinking water, comprising a 2,4-diaminopyrimidinein stable suspension, a suspending agent, and a sulfonamide, wherein thesulfonamide is selected from the compounds corresponding to thefollowing formula: wherein n equals zero or one and X, if present, is aphenyl moiety, and wherein R₁ through R₄

are, independently, selected from hydrogen and any organic moietycontaining up to 20 atoms.
 3. A palatable antimicrobial drugconcentrate, that may be orally administered to an animal in combinationwith its drinking water, comprising a 2,4-diaminopyrimidine in stablesuspension, a suspending agent, and a sulfonamide, wherein thesulfonamide is selected from the compounds corresponding to thefollowing formula:

wherein n equals zero or one and X, if present, is a phenyl moiety, andwherein R₅ through R₆ are, independently, selected from hydrogen and anyorganic moiety containing up to 20 atoms.
 4. A palatable antimicrobialdrug concentrate, that may be orally administered to an animal incombination with its drinking water, comprising a 2,4-diaminopyrimidinein stable suspension, a suspending agent, and a sulfonamide, wherein thesulfonamide is selected from the compounds corresponding to thefollowing formula:

wherein n equals zero or one and X, if present, is a phenyl moiety, andwherein R₁ through R₅ are, independently, selected from hydrogen and anyorganic moiety containing up to 20 atoms.
 5. The concentrate of claim 1,wherein said sulfonamide is sodium sulfadiazide.
 6. The concentrate ofclaim 2, wherein said sulfonamide is sodium sulfadiazide.
 7. Theconcentrate of claim 3, wherein said sulfonamide is sodium sulfadiazide.8. The concentrate of claim 4, wherein said sulfonamide is sodiumsulfadiazide.
 9. The concentrate of claim 1, wherein the suspendingagent is selected from the group consisting of polysaccharide gums andcellulosic derivatives.
 10. The concentrate of claim 2, wherein thesuspending agent is selected from the group consisting of polysaccharidegums and cellulosic derivatives.
 11. The concentrate of claim 3, whereinthe suspending agent is selected from the group consisting ofpolysaccharide gums and cellulosic derivatives.
 12. The concentrate ofclaim 4, wherein the suspending agent is selected from the groupconsisting of polysaccharide gums and cellulosic derivatives.
 13. Theconcentrate of claim 1 wherein the suspending agent is xanthan gum. 14.The concentrate of claim 1, wherein the suspending agent is present inthe amount of 0% to 5%, based on the entire concentrate.
 15. Theconcentrate of claim 1, additionally comprising one or more surfactants.16. The concentrate of claim 1, additionally comprising a polysorbatesurfactant.
 17. The concentrate of claim 1, wherein the compositionadditionally comprises one or more antioxidants, preservatives,sweeteners, and flavoring agents.
 18. The concentrate of claim 1comprising sodium sulfadiazine, trimethoprim, xanthan gum, a surfactant,and one or more compounds selected from the group consisting ofantioxidants, preservatives, sweeteners and flavoring agents.
 19. Theconcentrate of claim 1, wherein the room temperature shelf life is atleast 10 days.